JP7357386B2 - Application of the compound or its pharmaceutically acceptable salt, dimer or trimer in the preparation of drugs for cancer treatment - Google Patents
Application of the compound or its pharmaceutically acceptable salt, dimer or trimer in the preparation of drugs for cancer treatment Download PDFInfo
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- JP7357386B2 JP7357386B2 JP2021526673A JP2021526673A JP7357386B2 JP 7357386 B2 JP7357386 B2 JP 7357386B2 JP 2021526673 A JP2021526673 A JP 2021526673A JP 2021526673 A JP2021526673 A JP 2021526673A JP 7357386 B2 JP7357386 B2 JP 7357386B2
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- sotagliflodi
- cancer
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- gefitinib
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Description
本願は、2020年07月06日に中国特許庁へ提出された、出願番号202010643578.4、発明の名称「化合物又はその薬学的に許容される塩、二量体又は三量体のがん治療用医薬品の調製における応用」である中国特許出願に基づき優先権を主張し、その全内容は、援用により本明細書に組み込まれる。 This application is filed with the Chinese Patent Office on July 6, 2020, application number 202010643578.4, title of the invention "Cancer treatment of compounds or pharmaceutically acceptable salts, dimers or trimers thereof" Priority is claimed on the basis of the Chinese patent application ``Application in the Preparation of Medicinal Products for Use'', the entire contents of which are incorporated herein by reference.
本発明は、医薬技術分野に関し、特に化合物又はその薬学的に許容される塩、二量体又は三量体のがん治療用医薬品の調製における応用に関する。 The present invention relates to the field of pharmaceutical technology, and in particular to the application of compounds or their pharmaceutically acceptable salts, dimers or trimers in the preparation of medicaments for the treatment of cancer.
1.がんの疫学
非感染性疾患は、世界全体の主要な死因となるが、がんは、非感染性疾患の中で死亡率が最も高い疾患であり、社会の健康及び医療システムに大きな負担をもたらす。従来からがんの治療は、主に手術、放射線療法及び化学療法を施し、進行期のがんは化学療法を中心的に施す。伝統的な化学療法は標的化に劣るため、深刻な副作用がある。グリベックに代表される標的化学療法薬の登場により、患者への化学療法によって引き起こされる痛みが大幅に軽減されている。標的薬は、正常細胞とは異なるがん細胞の成長特性及び発現する分子について設計されて、例えば、グリベックは、慢性骨髄性白血病中の構成的に活性化されたチロシンキナーゼを特異的に標的とすることにより良好な治療効果を達成する(Flynn and Gerriets、 2020)。正常細胞とは異なるがん細胞のもう一つの際立った特徴は、代謝の変化である。急速な増殖のための細胞成分の需要と生存を維持するために必要なエネルギー供給のバランスをとるために、がん細胞は好気的解糖によるグルコースの使用を好むことは、Warburg効果と呼ばれる(Warburg、 1956)。好気的解糖は、グルコースを完全に酸化してATPをを生成することはできないが、DNAおよびタンパク質の合成のための中間代謝物を大量に生成することができ、がん細胞の増殖を促進する。従って、腫瘍細胞の糖代謝を標的にしてがん細胞の増殖を阻害することが可能である(Kroemer and Pouyssegur、 2008)。
1. Cancer Epidemiology Non-communicable diseases are a major cause of death worldwide, and cancer has the highest mortality rate among non-communicable diseases and places a heavy burden on social health and medical systems. bring. Traditionally, cancer treatment has mainly consisted of surgery, radiation therapy, and chemotherapy, with chemotherapy being primarily used for advanced stage cancers. Traditional chemotherapy is less targeted and has serious side effects. The advent of targeted chemotherapy drugs, such as Gleevec, has significantly reduced the pain caused by chemotherapy in patients. Targeted drugs are designed for the growth characteristics and molecules expressed by cancer cells that are different from normal cells; for example, Gleevec specifically targets constitutively activated tyrosine kinases in chronic myeloid leukemia. (Flynn and Gerriets, 2020). Another distinguishing feature of cancer cells that differs from normal cells is metabolic changes. To balance the demand for cellular components for rapid growth and the energy supply needed to maintain survival, cancer cells prefer to use glucose through aerobic glycolysis, known as the Warburg effect. (Warburg, 1956). Although aerobic glycolysis cannot completely oxidize glucose to produce ATP, it can produce large amounts of intermediate metabolites for DNA and protein synthesis, which can inhibit cancer cell proliferation. Facilitate. Therefore, it is possible to target the glucose metabolism of tumor cells to inhibit cancer cell proliferation (Kroemer and Pouyssegur, 2008).
2.ソタグリフロジ(sotagliflozin)及びがん治療
がん細胞は、主にグルコーストランスポーターを介して外部環境からグルコースを吸収し、グルコーストランスポーターは、2つの主要なファミリーに分けられ、1つは、拡散を補助することにより濃度勾配に沿ってグルコースを輸送するGLUTファミリーであり、もう1つはナトリウムイオンを共役輸送することによりグルコースを吸収するナトリウム-グルコース共輸送タンパクSGLTファミリーであり、該ファミリーのタンパク質は、ATPを消費することにより外部からグルコースを能動的に輸送し細胞で使用する(Navale and Paranjape,2016)。SGLTファミリーの2つの主なメンバーはは、SGLT1及びSGLT2であり、SGLT2は、主に腎臓の近位尿細管の前端に分布し、能動輸送により原尿中のグルコースの97%以上を血中に再吸収するが、SGLT1は主に小腸絨毛の上皮細胞と腎近位尿細管の遠位端に分布し、腸内の食物からグルコース、及び原尿中のSGLT2に吸収されて残った3%程度のグルコースを吸収する(Dominguez Rieg and Rieg,2019)。糖の吸収及び再吸収におけるSGLT1及びSGLT2の重要な役割により糖尿病治療の理想的な標的となる。現在、SGLT2を標的とするエンパグリフロジン、カナグリフロジン、ダパグリフロジンは、2型糖尿病の臨床的治療に優れた治療効果を示し、心血管疾患を軽減する効果もある。SGLT1のみを標的とするmizagliflozinは、臨床試験段階に入っている。SGLT1とSGLT2の両方を標的とするソタグリフロジは、欧州連合への販売が承認されている。
がん治療におけるソタグリフロジの用途はこれまでに報告されていない。
2. sotagliflozin and cancer treatment Cancer cells absorb glucose from the external environment mainly through glucose transporters, and glucose transporters are divided into two major families: one that assists in diffusion; One is the GLUT family, which transports glucose along the concentration gradient by By consuming ATP, glucose is actively transported from the outside and used by cells (Navale and Paranjape, 2016). The two main members of the SGLT family are SGLT1 and SGLT2, and SGLT2 is mainly distributed in the anterior end of the proximal tubule of the kidney and transports more than 97% of the glucose in raw urine into the blood through active transport. However, SGLT1 is mainly distributed in the epithelial cells of the small intestine villi and the distal end of the renal proximal tubule, and about 3% remains after being absorbed into glucose from food in the intestine and SGLT2 in raw urine. of glucose (Dominguez Rieg and Rieg, 2019). The important role of SGLT1 and SGLT2 in glucose absorption and reabsorption makes them ideal targets for diabetes treatment. Currently, empagliflozin, canagliflozin, and dapagliflozin, which target SGLT2, have shown excellent therapeutic effects in the clinical treatment of
The use of sotagliphology in cancer treatment has not been previously reported.
以上の状況に鑑み、本発明で解決されるべき技術的問題は、ソタグリフロジのがん治療用医薬品の調製における応用を提供する。 In view of the above circumstances, the technical problem to be solved by the present invention provides the application of Sotagliphology in the preparation of medicines for cancer treatment.
本発明は、式(I)で表される化合物又はその薬学的に許容される塩、二量体又は三量体の、がん治療用医薬品の調製における応用を提供する。
各R1Aは、独立して、アミノ基、エステル、アミド、チオール、カルボン酸、シアノ基、ハロゲン、ヒドロキシ基又は任意置換されたC1-4-アルコキシ基、C1-5-シクロアルキル基又は5員複素環であり、前記任意選択で置換されたのは、1つ又は複数のR1Bで置換されたことであり、各R1Bは、独立して、C1-4-アルキル基、ハロゲン又はヒドロキシ基であり、nは、0、1又は2であり、
各R2は、独立して、F又はOR2Aであり、ここで、各R2Aは、独立して、水素、C1-4-アルキル基又はアシル基であり、
各R3は、独立して、ハロゲン、ヒドロキシ基又は任意選択で置換されたC1-10-アルキル基又はC1-10-アルコキシ基であり、前記任意選択で置換されたのは、1つ又は複数のR3Aで置換されたことであり、
各R3Aは、独立して、アミノ基、エステル、アミド、チオール、カルボン酸、シアノ基、ハロゲン、ヒドロキシ基又は任意選択で置換されたC1-4-アルコキシ基、C1-5-シクロアルキル基又は5員複素環であり、前記任意選択で置換されたのは、1つ又は複数のR3Bで置換されたことであり、各R3Bは、独立して、C1-4-アルキル基、アミノ基、シアノ基、ハロゲン又はヒドロキシ基であり、pは、0、1又は2であり、
各R4は、独立して、R4A、-N(R4A)(R4B)、-OR4A、-SR4A、-S(O)R4A又は-S(O)2R4Aであり、
R4Aは、任意選択で置換されたC4-20-アルキル基又は4-20員ヘテロアルキル基であり、前記任意選択で置換されたのは、1つ又は複数のR4Cで置換されるとともに、別のR4Aの構成部分に連結されて、二量体又は三量体を与えることであり、R4Bは、水素又はR4Aであり、各R4Cは、独立して、アミノ基、アミノアシル基、アゾ基、カルボニル基、カルボキシル基、シアノ基、ホルミル基、グアニジノ基、ハロゲン、ヒドロキシ基、イミノイル基、イミノ基、イソチオシアネート、ニトリル、ニトロ基、ニトロソ基、ニトロキシル基、オキシ基、スルファニル基、スルフィニル基、スルホニル基、チオアルデヒド、チオシアネート、チオケトン、チオ尿素、尿素、或いはX1、X1-L1-X2又はX1-L1-X2-L2-X3であり、ここで、X1、X2及びX3は、それぞれ独立して、任意選択で置換されたC1-4-アルキル基、C1-6-シクロアルキル基、5-又は6員複素環又はアリール基であり、前記任意選択で置換されたのは、1つ又は複数のR4Dで置換されたことであり、且つL1及びL2は、それぞれ独立して、任意選択で置換されたC1-6-アルキル基又は1-10員ヘテロアルキル基であり、前記任意選択で置換されたのは、1つ又は複数のR4Eで置換されたことであり、各R4Dは、独立して、R4Eであるか、或いは1つ又は複数のR4Eで任意選択で置換されたC1-6-アルキル基であり、各R4Eは、独立して、アミノ基、アミノアシル基、アゾ基、カルボニル基、カルボキシル基、シアノ基、ホルミル基、グアニジノ基、ハロゲン、ヒドロキシ基、イミノイル基、イミノ基、イソチオシアネート、ニトリル基、ニトロ基、ニトロソ基、ニトロキシル基、オキソ、スルファニル基、スルフィニル基、スルホニル基、チオアルデヒド、チオシアネート、チオケトン又は尿素であり、且つmは、1、2又は3である。)
The present invention provides the application of a compound represented by formula (I) or a pharmaceutically acceptable salt, dimer or trimer thereof in the preparation of a medicament for treating cancer.
Each R 1A is independently an amino group, an ester, an amide, a thiol, a carboxylic acid, a cyano group, a halogen, a hydroxy group, or an optionally substituted C 1-4 -alkoxy group, a C 1-5 -cycloalkyl group, or The optionally substituted 5-membered heterocycle is substituted with one or more R 1B , each R 1B being independently a C 1-4 -alkyl group, a halogen or a hydroxy group, n is 0, 1 or 2,
Each R 2 is independently F or OR 2A , where each R 2A is independently hydrogen, a C 1-4 -alkyl group, or an acyl group;
Each R 3 is independently a halogen, a hydroxy group or an optionally substituted C 1-10 -alkyl or C 1-10 -alkoxy group, wherein said optionally substituted one or is substituted with multiple R 3A ,
Each R 3A is independently an amino group, an ester, an amide, a thiol, a carboxylic acid, a cyano group, a halogen, a hydroxy group, or an optionally substituted C 1-4 -alkoxy group, a C 1-5 -cycloalkyl group. or a 5-membered heterocycle, said optionally substituted is substituted with one or more R 3B , each R 3B being independently a C 1-4 -alkyl group. , an amino group, a cyano group, a halogen or a hydroxy group, p is 0, 1 or 2,
Each R 4 is independently R 4A , -N(R 4A )(R 4B ), -OR 4A , -SR 4A , -S(O)R 4A or -S(O) 2 R 4A ,
R 4A is an optionally substituted C 4-20 -alkyl group or a 4-20 membered heteroalkyl group, said optionally substituted being substituted with one or more R 4C and , is linked to another R 4A component to give a dimer or trimer, R 4B is hydrogen or R 4A , and each R 4C is independently an amino group, an aminoacyl group, azo group, carbonyl group, carboxyl group, cyano group, formyl group, guanidino group, halogen, hydroxy group, iminoyl group, imino group, isothiocyanate, nitrile, nitro group, nitroso group, nitroxyl group, oxy group, sulfanyl group , sulfinyl group, sulfonyl group, thioaldehyde, thiocyanate, thioketone, thiourea, urea, or X 1 , X 1 -L 1 -X 2 or X 1 -L 1 -X 2 -L 2 -X 3 , where and X 1 , X 2 and X 3 are each independently an optionally substituted C 1-4 -alkyl group, C 1-6 -cycloalkyl group, 5- or 6-membered heterocycle or aryl group and said optionally substituted is substituted with one or more R 4D , and L 1 and L 2 are each independently optionally substituted C 1- 6 -alkyl group or 1-10 membered heteroalkyl group, said optionally substituted being substituted with one or more R 4E , each R 4D being independently R 4E or a C 1-6 -alkyl group optionally substituted with one or more R 4E , where each R 4E is independently an amino group, an aminoacyl group, an azo group, a carbonyl group. , carboxyl group, cyano group, formyl group, guanidino group, halogen, hydroxy group, iminoyl group, imino group, isothiocyanate, nitrile group, nitro group, nitroso group, nitroxyl group, oxo, sulfanyl group, sulfinyl group, sulfonyl group, It is thioaldehyde, thiocyanate, thioketone or urea, and m is 1, 2 or 3. )
本発明では、前記式(I)で表される化合物又はその薬学的に許容される塩、二量体又は三量体で治療されるがんは、膀胱がん、血液がん、骨がん、脳がん、乳がん、中枢神経系がん、子宮頸がん、結腸がん、子宮内膜がん、食道がん、胆嚢がん、胃腸がん、外生殖器がん、泌尿生殖器がん、頭部がん、腎臓がん、喉頭がん、肝臓がん、筋肉組織がん、頸部がん、口腔または鼻粘膜がん、卵巣がん、前立腺がん、皮膚がん、脾臓がん、小腸がん、大腸がん、胃がん、精巣がん及び/又は甲状腺がんを含む。
本発明では、R1は、メチル基であり、n=0、R2はいずれも-OHであり、p=1、R3は、Clであり、m=1、R4は、エトキシ基である。
幾つかの実施例において、前記式(I)で表される化合物は、ソタグリフロジであり、その構造が式(II)に示すとおりである。
In the present invention, R 1 is a methyl group, n=0, R 2 are all -OH, p=1, R 3 is Cl, m=1, and R 4 is an ethoxy group. be.
In some embodiments, the compound represented by formula (I) is sotagliflodi, and its structure is as shown in formula (II).
本発明では、前記治療は、腫瘍細胞増殖の阻害及び/又は腫瘍体積の阻害を含む。幾つかの実施例において、肺がん細胞A549、肝臓がん細胞HepG2、前立腺がんDU145細胞、乳がんMCF-7細胞、食道がんKYSE30細胞、胃がんHGC-27細胞、胆管がんRBE細胞、卵巣がんSKOV3細胞、子宮頸がんHeLa細胞を使用して腫瘍細胞に対するソタグリフロジの阻害効果を検証し、細胞実験は、ソタグリフロジが腫瘍細胞に対して一定の阻害効果を持ち、IC50値は、順に71.57μM、115.7μM、、40.77μM、64.84μM、82.27μM、48.54μM、182.5μM、84.49μM、82.11μMであることを示す。動物実験では、ソタグリフロジは腫瘍体積を阻害する優れた効果を示し、溶剤対照群に対して有意差が認められ、p<0.05である。
本発明は、さらに、式(I)で表される化合物又はその薬学的に許容される塩、二量体又は三量体の、抗腫瘍薬の耐性を逆転させる製剤の調製における応用を提供する。幾つかの具体的な実施例において、本発明は、抗腫瘍薬の耐性を逆転させる製剤の調製におけるソタグリフロジの応用を提供する。
In the present invention, said treatment comprises inhibition of tumor cell proliferation and/or inhibition of tumor volume. In some examples, lung cancer cells A549, liver cancer cells HepG2, prostate cancer DU145 cells, breast cancer MCF-7 cells, esophageal cancer KYSE30 cells, gastric cancer HGC-27 cells, bile duct cancer RBE cells, ovarian cancer The inhibitory effect of Sotagliflodi on tumor cells was verified using SKOV3 cells and cervical cancer HeLa cells, and the cell experiment showed that Sotagliflodi had a certain inhibitory effect on tumor cells, and the IC50 value was 71.57 μM. , 115.7 μM, 40.77 μM, 64.84 μM, 82.27 μM, 48.54 μM, 182.5 μM, 84.49 μM, 82.11 μM. In animal experiments, Sotagliflodi showed excellent efficacy in inhibiting tumor volume, with a significant difference compared to the solvent control group, p<0.05.
The present invention further provides the application of a compound of formula (I) or a pharmaceutically acceptable salt, dimer or trimer thereof in the preparation of a formulation for reversing the resistance of antitumor drugs. . In some specific embodiments, the present invention provides the application of sotagliphology in the preparation of formulations that reverse anti-tumor drug resistance.
本発明は、さらに、式(I)で表される化合物又はその薬学的に許容される塩、二量体又は三量体を投与する、抗腫瘍薬の耐性を逆転させる方法を提供する。幾つかの具体的な実施例において、本発明は、さらに、ソタグリフロジを投与する、抗腫瘍薬の耐性を逆転させる方法を提供する。
本発明では、式(I)で表される化合物又はその薬学的に許容される塩、二量体又は三量体は、抗腫瘍薬の耐性を逆転させるのに使用されることができ、前記抗腫瘍薬は、チロシンキナーゼ阻害剤である。
本発明では、前記チロシンキナーゼ阻害剤は、EGFR阻害剤、c-Kit、c-Met、c-Ret、Raf、PDGFR、BTK、PKA/C、FGFR阻害剤、VEGFR阻害剤を含む。
The present invention further provides a method for reversing antitumor drug resistance, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt, dimer or trimer thereof. In some specific embodiments, the invention further provides a method of reversing anti-tumor drug resistance, comprising administering sotagliflodi.
In the present invention, the compound represented by formula (I) or a pharmaceutically acceptable salt, dimer or trimer thereof can be used to reverse the resistance of an antitumor drug, Antitumor drugs are tyrosine kinase inhibitors.
In the present invention, the tyrosine kinase inhibitor includes EGFR inhibitor, c-Kit, c-Met, c-Ret, Raf, PDGFR, BTK, PKA/C, FGFR inhibitor, and VEGFR inhibitor.
幾つかの実施例において、前記EGFR阻害剤は、ゲフィチニブ、エルロチニブ、アファチニブ、ラパチニブトシル酸塩、ゲニステイン、ラパチニブ、サピチニブ(Sapitinib)、ダフネチン、ダコミチニブ、バルリチニブ、イコチニブ、リドカイン塩酸塩、オシメルチニブメシル酸塩、オシメルチニブ、ポジオチニブ(Poziotinib)、ナザルチニブ、AZD3759、オルムチニブ、アビチニブ、ネラチニブ、ラゼルチニブを含む。
前記c-Met阻害剤は、カボザンチニブを含む。
前記PKA/C阻害剤は、ダフネチンを含む。
前記BTK阻害剤は、オルムチニブを含む。
前記c-Ret阻害剤は、レゴラフェニブ水合物、レゴラフェニブを含む。
前記Raf阻害剤は、レゴラフェニブ水合物を含む。
前記FGFR阻害剤は、4-[(1E)-2-[5-[(1R)-1-(3,5-ジクロロ-4-ピリジル)エトキシ]-1H-インダゾール-3-イル]ビニル]-1H-ピラゾール-1-エタノール;ニンテダニブ、ニンテダニブエタンスルホン酸塩、ポナチニブ、ブリバニブ、ブリバニブアラニナートを含む。
前記c-Kit阻害剤は、アキシチニブ、パゾパニブ、パゾパニブ塩酸塩、レゴラフェニブ水合物、スニチニブリンゴ酸塩、スニチニブ、シトラバチニブ、テラチニブを含む。
前記PDGFR阻害剤は、アキシチニブ、チボザニブ、テラチニブ、ニンテダニブ、ニンテダニブエタンスルホン酸塩、パゾパニブ、パゾパニブ塩酸塩、ポナチニブを含む。
In some examples, the EGFR inhibitor is gefitinib, erlotinib, afatinib, lapatinib tosylate, genistein, lapatinib, sapitinib, daphnetin, dacomitinib, vallitinib, icotinib, lidocaine hydrochloride, osimertinib mesylate. salts, osimertinib, poziotinib, nazartinib, AZD3759, olmutinib, avitinib, neratinib, lazertinib.
The c-Met inhibitor includes cabozantinib.
The PKA/C inhibitor includes daphnetin.
The BTK inhibitor includes olmutinib.
The c-Ret inhibitor includes regorafenib hydrate and regorafenib.
The Raf inhibitor includes regorafenib hydrate.
The FGFR inhibitor is 4-[(1E)-2-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]vinyl]- 1H-pyrazole-1-ethanol; includes nintedanib, nintedanib ethanesulfonate, ponatinib, brivanib, brivanib alaninate.
The c-Kit inhibitors include axitinib, pazopanib, pazopanib hydrochloride, regorafenib hydrate, sunitinib malate, sunitinib, sitravatinib, and teratinib.
The PDGFR inhibitors include axitinib, tivozanib, teratinib, nintedanib, nintedanib ethanesulfonate, pazopanib, pazopanib hydrochloride, ponatinib.
前記VEGFR阻害剤は、アパチニブ、アキシチニブ、ニンテダニブ、セジラニブ、パゾパニブ塩酸塩、スニチニブリンゴ酸塩、ブリバニブ、カボザンチニブ、ブリバニブアラニナート、レンバチニブ、レゴラフェニブ、ENMD-2076、ENMD-2076酒石酸塩、チボザニブ、ポナチニブ、フルキンチニブ、テラチニブ、タキシフォリン、パゾパニブ、カボザンチニブリンゴ酸塩、ビタミンE、レゴラフェニブ水合物、ニンテダニブエタンスルホン酸塩、レンバチニブメシル酸塩、セジラニブマレイン酸塩、4-[(1E)-2-[5-[(1R)-1-(3,5-ジクロロ-4-ピリジル)エトキシ]-1H-インダゾール-3-イル]ビニル]-1H-ピラゾール-1-エタノール、スニチニブ、シトラバチニブ、アンロチニブ、ソラフェニブ、バンデタニブ及びベバシズマブなどのVEGFRを標的とするモノクローナル抗体薬を含む。
本発明では、ソタグリフロによる抗腫瘍薬の耐性の逆転を検証するために使用される抗腫瘍薬は、マルチターゲット型キナーゼ阻害剤、チボザニブ、ゲニステイン、ポナチニブ、ダフネチン、ダコミチニブ、バルリチニブ、イコチニブ、オシメルチニブメシル酸塩、オシメルチニブ、ナザルチニブ、AZD3759、アンロチニブ、アビチニブ又はラゼルチニブ、リドカイン塩酸塩、4-[(1E)-2-[5-[(1R)-1-(3,5-ジクロロ-4-ピリジル)エトキシ]-1H-インダゾール-3-イル]ビニル]-1H-ピラゾール-1-エタノール、アキシチニブ、ニンテダニブ、セジラニブ、パゾパニブ塩酸塩、スニチニブリンゴ酸塩、ブリバニブ、カボザンチニブ、ブリバニブアラニナート、レンバチニブ、レゴラフェニブ、ENMD-2076 酒石酸塩、テラチニブ、パゾパニブ、カボザンチニブリンゴ酸塩、レゴラフェニブ水和物、ニンテダニブエタンスルホン酸塩、レンバチニブメシル酸塩、セジラニブマレイン酸塩、フルキンチニブ、スニチニブ、オルムチニブ、シトラバチニブ、バンデタニブ、ゲフィチニブ、アファチニブ、アパチニブ、エルロチニブ又はソラフェニブ、タキシフォリン又はビタミンEの少なくとも1つである。
The VEGFR inhibitors include apatinib, axitinib, nintedanib, cediranib, pazopanib hydrochloride, sunitinib malate, brivanib, cabozantinib, brivanib alaninate, lenvatinib, regorafenib, ENMD-2076, ENMD-2076 tartrate, tivozanib, ponatinib, Fruquintinib, teratinib, taxifolin, pazopanib, cabozantinib malate, vitamin E, regorafenib hydrate, nintedanib ethanesulfonate, lenvatinib mesylate, cediranib maleate, 4-[(1E) -2-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]vinyl]-1H-pyrazole-1-ethanol, sunitinib, citravatinib, Includes monoclonal antibody drugs targeting VEGFR such as anlotinib, sorafenib, vandetanib and bevacizumab.
In the present invention, the anti-tumor drugs used to verify the reversal of anti-tumor drug resistance by Sotaglifuro are multi-targeted kinase inhibitors, tivozanib, genistein, ponatinib, daphnetin, dacomitinib, vallitinib, icotinib, osimertinib. Mesylate, osimertinib, nazartinib, AZD3759, anlotinib, avitinib or lazertinib, lidocaine hydrochloride, 4-[(1E)-2-[5-[(1R)-1-(3,5-dichloro-4-pyridyl) ethoxy]-1H-indazol-3-yl]vinyl]-1H-pyrazole-1-ethanol, axitinib, nintedanib, cediranib, pazopanib hydrochloride, sunitinib malate, brivanib, cabozantinib, brivanib alaninate, lenvatinib, regorafenib, ENMD-2076 tartrate, teratinib, pazopanib, cabozantinib malate, regorafenib hydrate, nintedanib ethanesulfonate, lenvatinib mesylate, cediranib maleate, fruquintinib, sunitinib, olmutinib, At least one of sitravatinib, vandetanib, gefitinib, afatinib, apatinib, erlotinib or sorafenib, taxifolin or vitamin E.
本発明の実施例では、まず、ゲフィチニブ(60μM)耐性細胞株を構築し、次いで本発明で得られたゲフィチニブ耐性細胞株に30μM ゲフィチニブとソタグリフロジとの組成物を加えて、その細胞株を依然として効果的に殺傷することができる。これは、ソタグリフロジとゲフィチニブの併用がゲフィチニブに対する腫瘍細胞の薬剤耐性を逆転させることを示した。
本発明は、さらに、式(I)で表される化合物又はその薬学的に許容される塩、二量体又は三量体、及び薬学的に許容される添加剤を含むがん治療用医薬品を提供する。
本発明に記載の医薬品は、さらに、抗腫瘍効果を有する他の医薬品、例えば、チロシンキナーゼ阻害剤を含む。
前記医薬品の投与経路は、経口投与であり、その剤形は顆粒剤、丸剤、散剤、錠剤、カプセル剤、経口液剤又はシロップ剤を含む。
発明で提供される幾つかの実施例において、カプセル剤は、ハードカプセル剤又はソフトカプセル剤である。
本発明で提供される幾つかの実施例において、錠剤は、内服用錠剤又は口腔用錠剤である。
In an example of the present invention, a gefitinib (60 μM) resistant cell line was first constructed, and then a composition of 30 μM gefitinib and sotagliflozhy was added to the gefitinib resistant cell line obtained in the present invention to make the cell line still effective. can be killed or injured. This showed that the combination of sotagliflodi and gefitinib reversed the drug resistance of tumor cells to gefitinib.
The present invention further provides a drug for cancer treatment containing a compound represented by formula (I) or a pharmaceutically acceptable salt, dimer or trimer thereof, and a pharmaceutically acceptable additive. provide.
The medicaments according to the invention further include other medicaments with antitumor effects, such as tyrosine kinase inhibitors.
The route of administration of the drug is oral administration, and its dosage forms include granules, pills, powders, tablets, capsules, oral liquids, and syrups.
In some embodiments provided in the invention, the capsule is a hard capsule or a soft capsule.
In some embodiments provided by the present invention, the tablet is an oral or buccal tablet.
錠剤とは、経口投与用錠剤を指し、このような錠剤のほとんどに含まれる薬物は、消化管から吸収されて効果を発揮し、錠剤の一部に含まれる薬物は消化管で局所的に作用することもある。本発明で提供される幾つかの実施例において、錠剤は、一般的な圧縮錠、分散錠、発泡錠、チュアブル錠、コーティング錠又は徐放性錠剤である。
前記医薬品は、さらに、フルーツパウダー、食用フレーバー、甘味料、酸味料、充填剤、潤滑剤、防腐剤、懸濁助剤、食品着色料、希釈剤、乳化剤、崩壊剤または可塑剤の1つ又は2つ以上の混合物を含む薬学的に許容される添加剤を含む。
Tablets refer to tablets for oral administration; the drugs contained in most of these tablets are absorbed through the gastrointestinal tract to exert their effects, while the drugs contained in some tablets act locally in the gastrointestinal tract. Sometimes I do. In some embodiments provided by the present invention, the tablet is a conventional compressed tablet, dispersible tablet, effervescent tablet, chewable tablet, coated tablet, or sustained release tablet.
The pharmaceutical product may further contain one or more of fruit powders, edible flavors, sweeteners, acidulants, fillers, lubricants, preservatives, suspension aids, food colorants, diluents, emulsifiers, disintegrants or plasticizers. and pharmaceutically acceptable excipients, including mixtures of two or more.
本発明は、さらに、本発明に記載の医薬品を投与するがんの治療法を提供する。
本発明は、式(I)で表される化合物又はその薬学的に許容される塩、二量体又は三量体のがん治療用医薬品の調製における応用を提供し、複数種の腫瘍細胞にて阻害効果の検証を行い、結果は、式(I)で表される化合物は腫瘍細胞に対して一定の阻害効果を有し、IC50値が40.77μM~182.5μMになることを示した。肝臓がん細胞及び肺がん細胞を使用して担がんマウスモデルを作製し、動物実験では、式(I)で表される化合物は腫瘍体積を阻害する優れた効果を示し、溶剤対照群に対して有意差が認められ、p<0.05である。
The present invention further provides a method for treating cancer comprising administering a medicament according to the present invention.
The present invention provides an application of the compound represented by formula (I) or its pharmaceutically acceptable salt, dimer or trimer in the preparation of a drug for cancer treatment, and The results showed that the compound represented by formula (I) had a certain inhibitory effect on tumor cells, with an IC50 value of 40.77 μM to 182.5 μM. . A tumor-bearing mouse model was created using liver cancer cells and lung cancer cells, and in animal experiments, the compound represented by formula (I) showed an excellent effect on inhibiting tumor volume, and compared to a solvent control group. A significant difference was observed, p<0.05.
本発明は、ソタグリフロジのがん治療用医薬品の調製における応用を提供する。当業者は、本明細書を参照し、プロセスパラメータを適切に改良して実現することができる。特に、全ての類似する置換及び改良は、当業者にとっては自明になり、これらは本発明に含まれることを指摘すべきである。本発明に係る方法及び応用は、好ましい実施形態により説明されているが、当業者は、本発明の内容、精神および範囲から逸脱することなく、本明細書に係る方法及び応用に改良又は適当な変更及び組み合わせを加え、本発明に係る技術を実現して適用することができる。
本発明において特に別段の記載がない限り、本発明に含まれる全ての技術的及び科学的用語の意味は、当業者によって一般的に理解されているものと一致することを意図している。本発明で使用される技術は、当技術分野で一般に理解されている技術を指すことを意図し、当業者に明らかな技術的変更又は同等技術の置換を含む。以下の用語は当業者によって十分に理解されていると考えられているが、本発明をよりよく説明するために、以下の定義が依然として示されている。
本明細書で使用される「含む」、「含める」、「有する」、「含有」又は「関する」という用語及び本明細書での他の変形は、包含式又は開放式であり、他の挙げられていない要素又は方法及び手順を除きかない。
The present invention provides the application of Sotagliphology in the preparation of medicaments for cancer treatment. Those skilled in the art can refer to this specification and appropriately modify and implement the process parameters. In particular, it should be pointed out that all similar substitutions and modifications that become obvious to a person skilled in the art are included in the invention. Although the methods and applications of the present invention have been described in terms of preferred embodiments, those skilled in the art will appreciate that modifications or adaptations can be made to the methods and applications herein without departing from the spirit, spirit and scope of the invention. Modifications and combinations may be made to realize and apply the techniques of the present invention.
Unless specifically stated otherwise in the present invention, the meanings of all technical and scientific terms included in the present invention are intended to be consistent with that commonly understood by one of ordinary skill in the art. The techniques used in the present invention are intended to refer to techniques as commonly understood in the art, and include technical modifications or substitutions of equivalent techniques that would be obvious to those skilled in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are still provided to better explain the present invention.
As used herein, the terms "comprising,""including,""having,""containing," or "relating to" and other variations herein are inclusive or open, and other Exclude elements or methods and procedures that are not specified.
従って、本発明は、SGLTファミリーの2つの最も重要で、がん細胞で高度に発現されるメンバーであるSGLT1及びSGLT2の二重阻害剤ソタグリフロジ及びそれのTKIを含有する組成物の、がん治療薬の調製における用途に関する。
本明細書で使用される「治療」という用語は、本発明の医薬品を投与した後に患有疾患又は病状に罹患している実験動物に前記症状が部分的又は完全に軽減されるか、または治療後に悪化し続けないことを示す。従って、治療は、治癒を含む。
本明細書で使用される「治療効果」とは、治療によって引き起こされる効果を指し、細胞レベルでは、細胞増殖の阻害率または死細胞率として現れ、動物レベルでは、その変化、通常、疾患や病状の軽減又は改善、疾患や病状の治癒として現れ、本発明では、医薬品の有効性によれば、腫瘍増殖阻害率が60%を超えるとともに治療群と対照群の間での腫瘍体積又は重量の統計的有意差p値が0.05未満であることを採用する。
Therefore, the present invention discloses the use of compositions containing the dual inhibitor Sotagliflodi and its TKIs of SGLT1 and SGLT2, the two most important and highly expressed members of the SGLT family in cancer cells, for the treatment of cancer. Concerning use in the preparation of medicines.
As used herein, the term "treatment" refers to a condition in which an experimental animal suffering from a disease or condition is partially or completely relieved of its symptoms after administration of the medicament of the present invention, or Indicates that it does not continue to worsen afterward. Accordingly, treatment includes curing.
As used herein, "therapeutic effect" refers to an effect caused by a treatment, manifested at the cellular level as a rate of inhibition of cell proliferation or cell death, and at the animal level, a change in that, typically a disease or condition. According to the present invention, according to the efficacy of the drug, the tumor growth inhibition rate exceeds 60% and the statistics of tumor volume or weight between the treatment group and the control group. A statistically significant difference p value of less than 0.05 is adopted.
本明細書で使用される「細胞増殖阻害率」とは、薬物治療後に、対照群の吸光度の平均値に対する治療群の細胞のMTT染色を行った吸光度の平均値の比を意味し、「腫瘍増殖阻害率」とは、薬物治療後に対照群の体積又は重量の平均値に対する治療群の腫瘍体積又は重量の平均値の比を指す。
一実施形態において、前記ソタグリフロジは、対象のがんを治療するために使用される。
本明細書で使用される「がん」という用語とは、遺伝物質の変化による上皮細胞の悪性増殖を指す。前記がん症は、膀胱がん、血液がん、骨がん、脳がん、乳がん、中枢神経系がん、子宮頸がん、結腸がん、子宮内膜がん、食道がん、胆嚢がん、胃腸がん、外生殖器がん、泌尿生殖器がん、頭部がん、腎臓がん、喉頭がん、肝臓がん、筋肉組織がん、頸部がん、口腔または鼻粘膜がん、卵巣がん、前立腺がん、皮膚がん、脾臓がん、小腸がん、大腸がん、胃がん、精巣がん及び/又は甲状腺がんを含む。
本発明で使用される試験材は、いずれも市場で購入する可能な普通の市販品である。
本願の実施例では、関係する医薬品及びその英語名を表1に示す。
As used herein, the term "cell growth inhibition rate" refers to the ratio of the average absorbance of MTT-stained cells in the treatment group to the average absorbance of the control group after drug treatment; "Growth inhibition rate" refers to the ratio of the average tumor volume or weight of the treated group to the average volume or weight of the control group after drug treatment.
In one embodiment, the sotagliphology is used to treat cancer in a subject.
The term "cancer" as used herein refers to a malignant growth of epithelial cells due to changes in genetic material. The cancer diseases include bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, and gallbladder cancer. Cancer, gastrointestinal cancer, external genital tract cancer, genitourinary tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, muscle tissue cancer, neck cancer, oral or nasal mucosa cancer , ovarian cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, colon cancer, stomach cancer, testicular cancer and/or thyroid cancer.
The test materials used in the present invention are all commercially available products that can be purchased on the market.
In the Examples of the present application, related pharmaceuticals and their English names are shown in Table 1.
以下、実施例により本発明をさらに説明する。 The present invention will be further explained below with reference to Examples.
実施例1 腫瘍細胞に対するソタグリフロジの阻害効果
前立腺がんDU145細胞、乳がんMCF-7細胞、食道がんKYSE30細胞、胃がんHGC-27細胞、胆管がんRBE細胞、卵巣がんSKOV3細胞、子宮頸がんHela細胞は、腫瘍細胞に対するソタグリフロジの阻害効果を検証した。その方法は、細胞が80%の密度に成長してから、トリプシン消化され、継代され、96ウェルプレートに5000cells/ウェルで塗り広げ、24時間後、対応する濃度の医薬品を含む培地に交換し、48時間後、MTT法により各濃度における吸光度を検出する。
実験は、以下の各群に分けられた。
対照群:薬物を添加せず、正常培地のみを使用して細胞を培養した。
ソタグリフロジ被験群:各細胞の培地にソタグリフロジを添加して細胞を処置し、複数の異なる濃度を設定した。
培養終了後、各濃度における吸光度を対照群の吸光度で割ることにより、細胞増殖阻害率を算出し、各腫瘍細胞に対するソタグリフロジのIC50値を算出した結果は、図1-a~図1-gに示した。図中では、ソタグリフロジの濃度を横軸とし、細胞増殖阻害率を縦軸とした結果は、ソタグリフロジは各種の腫瘍細胞に対していずれも一定の阻害効果を有することを示した。
Example 1 Inhibitory effect of sotagliphology on tumor cells Prostate cancer DU145 cells, breast cancer MCF-7 cells, esophageal cancer KYSE30 cells, gastric cancer HGC-27 cells, bile duct cancer RBE cells, ovarian cancer SKOV3 cells, cervical cancer HeLa cells were used to verify the inhibitory effect of sotagliphology on tumor cells. The method was that cells were grown to 80% confluency, then tryptic digested, passaged, spread in 96-well plates at 5000 cells/well, and 24 hours later, the medium was changed to the medium containing the corresponding concentration of drug. , 48 hours later, the absorbance at each concentration is detected by the MTT method.
The experiment was divided into the following groups.
Control group: Cells were cultured using only normal medium without adding drugs.
Sotagliphology test group: Cells were treated by adding Sotagliphology to the culture medium of each cell, and several different concentrations were established.
After culturing, the cell growth inhibition rate was calculated by dividing the absorbance at each concentration by the absorbance of the control group, and the IC50 value of Sotagliphology for each tumor cell was calculated. The results are shown in Figures 1-a to 1-g. Indicated. In the figure, the horizontal axis represents the concentration of Sotagliphology and the vertical axis represents the cell growth inhibition rate. The results show that Sotagliphology has a certain inhibitory effect on various tumor cells.
実施例2 ソタグリフロジとゲフィチニブの併用
1、ソタグリフロジの安全な濃度の特定
セレックバイオテック株式会社からソタグリフロジを購入し、in vitroがん細胞増殖阻害試験を行い、まず、正常なヒト臍帯上皮細胞を使用して測定し、ソタグリフロジは濃度が80μMを超えると大きな細胞毒性を示し、80μM未満になると細胞増殖阻害として現れるため、正常な細胞への影響を与えないように本実験の後続の組成物で使用されるソタグリフロジの濃度はいずれも80μM未満である。
2、腫瘍細胞に対する併用投与の阻害効果
ゲフィチニブ及びソタグリフロジの標的であるEGFR及びSGLT1/2の組織分布特性に基づいて、肺がん細胞株A549、結腸・直腸がん細胞株LoVo、HT29、SW620、HCT116、子宮頸がんHeLa、卵巣がんSKOV3、胃がんHGC27、胆管がんRBE、食道がんKYSE30などを選択して実験的に検証した。その方法は、細胞が80%の密度に成長してから、トリプシン消化され、継代され、96ウェルプレートに5000cells/ウェルで塗り広げ、24時間後、対応する濃度の医薬品を含む培地に交換し、48時間後、MTT法により各濃度における吸光度を検出する。
実験は、以下の各群に分けられた。
対照群:薬物を添加せず、正常培地のみを使用して細胞を培養した。
ゲフィチニブ被験群:培地にゲフィチニブのみを添加して細胞を処置し、4つの異なる濃度をそれぞれ5μM、10μM、20μM、30μMに設定して処置した。
ゲフィチニブ+ソタグリフロジの併用投与被験群:培地にソタグリフロジ(20μM)及びゲフィチニブを添加して細胞を処置し、4つの異なる濃度を設定して処置し、ここで、ゲフィチニブの濃度は、それぞれ5μM、10μM、20μM、30μMである。
培養終了後、各濃度における吸光度を対照群の吸光度で割ることにより、細胞増殖阻害率を算出した結果は、図2-a~図2-eに示した。図中では、ゲフィチニブの濃度を横軸とし、細胞増殖阻害率を縦軸とした結果は、ゲフィチニブを単独使用すると腫瘍細胞に対する阻害効果が限られているが、2剤併用は、腫瘍に対する阻害効果を向上させるのに有益であることを示した。
Example 2 Combination of sotagliflodi and
2. Inhibitory effect of combined administration on tumor cells Based on the tissue distribution characteristics of EGFR and SGLT1/2, which are the targets of gefitinib and sotagliflodi, lung cancer cell line A549, colorectal cancer cell line LoVo, HT29, SW620, HCT116, Cervical cancer HeLa, ovarian cancer SKOV3, gastric cancer HGC27, bile duct cancer RBE, and esophageal cancer KYSE30 were selected and experimentally verified. The method was that cells were grown to 80% confluency, then tryptic digested, passaged, spread in 96-well plates at 5000 cells/well, and 24 hours later, the medium was changed to the medium containing the corresponding concentration of drug. , 48 hours later, the absorbance at each concentration is detected by the MTT method.
The experiment was divided into the following groups.
Control group: Cells were cultured using only normal medium without adding drugs.
Gefitinib test group: Cells were treated with gefitinib alone added to the medium and treated at four different concentrations: 5 μM, 10 μM, 20 μM, and 30 μM, respectively.
Combined administration of gefitinib + sotagliflodi Test group: Cells were treated by adding sotagliflodi (20 μM) and gefitinib to the culture medium, and treated at four different concentrations, where the concentration of gefitinib was 5 μM, 10 μM, respectively. They are 20 μM and 30 μM.
After the culture was completed, the cell growth inhibition rate was calculated by dividing the absorbance at each concentration by the absorbance of the control group. The results are shown in FIGS. 2-a to 2-e. In the figure, the concentration of gefitinib is plotted on the horizontal axis and the cell growth inhibition rate is plotted on the vertical axis. The results show that when gefitinib is used alone, the inhibitory effect on tumor cells is limited, but when the two drugs are used in combination, it has an inhibitory effect on tumor cells. It has been shown that it is useful for improving
3、併用投与によるIC50値の測定
肺がん細胞株A549を例として、ゲフィチニブ+ソタグリフロジの併用投与によるIC50値を検出し、その実験は、以下の各群に分けられた。
ゲフィチニブ被験群(図2-a-1):培地にゲフィチニブのみを添加して細胞を処置し、1時間インキュベートした後に細胞生存率を検出した。それぞれ0μM、10μM、20μM、30μM、40μM、50μMの6つの濃度勾配を設定した。結果は、A549細胞に対するゲフィチニブのIC50値は24.42μMであることが分かった。
ソタグリフロジ被験群(図2-a-2):培地にソタグリフロジのみを添加して細胞を処置し、1時間インキュベートした後、細胞生存率を検出した。それぞれ0μM、10μM、30μM、40μM、50μM、60μMの6つの濃度勾配を設定した。結果は、A549細胞に対するソタグリフロジのIC50値は73.04μMであることを示した。
ゲフィチニブ+ソタグリフロジの併用投与被験群1(図2-a-3):培地にソタグリフロジ(10μM)及びゲフィチニブを添加して細胞を処置し、1時間インキュベートした後、細胞生存率を検出した。ゲフィチニブは、それぞれ0μM、10μM、20μM、30μM、50μM、60μMの6つの異なる濃度を設定して処置した。結果は、A549細胞に対する該被験群のIC50値は17.03μMであることを示した。
ゲフィチニブ+ソタグリフロジの併用投与被験群2(図2-a-4):培地にソタグリフロジ(20μM)及びゲフィチニブを添加して細胞を処置し、2時間インキュベートした後、細胞生存率を検出した。ゲフィチニブは、それぞれ0μM、10μM、20μM、30μM、40μMの5つの異なる濃度を設定して処置した。結果は、A549細胞に対する該被験群のIC50値は12.71μMであることを示した。
ゲフィチニブ+ソタグリフロジの併用投与被験群3(図2-a-5):培地にソタグリフロジ(30μM)及びゲフィチニブを添加して細胞を処置し、1時間インキュベートした後、細胞生存率を検出した。ゲフィチニブは、それぞれ0μM、10μM、20μM、30μM、40μM、50μMの6つの異なる濃度を設定して処置した。結果は、A549細胞に対する該被験群のIC50値は9.318μMであることを示した。
この結果は、ソタグリフロジとゲフィチニブとの組成物を使用すると、A549細胞に対するゲフィチニブの阻害率が顕著に向上し、IC50が単剤の半分未満に減少したため、ソタグリフロジの安全な濃度範囲内での併用効果が単剤のそれぞれの効果よりも優れたことを示した。他の細胞株の検証結果は、図面(2f-2j)を参照し、このようなソタグリフロジとの併用投与によるEGFRを標的とするEGFR-TKIの薬効への増強能力は、ゲフィチニブの単一の薬剤に限定されないことに言及すべきであり、図2k、図2lにおいて、本発明はA549細胞を例として他の2つのEGFR阻害剤であるアファチニブ及びエルロチニブをさらに検証しており、結果は、安全な用量のソタグリフロジの加えがアファチニブ及びエルロチニブのIC50値を効果的に低減させることができることを示した。
3. Measurement of IC50 value due to combined administration Taking lung cancer cell line A549 as an example, IC50 value due to combined administration of gefitinib + sotagliflodi was detected, and the experiment was divided into the following groups.
Gefitinib test group (FIG. 2-a-1): Cells were treated by adding only gefitinib to the medium, and cell viability was detected after incubation for 1 hour. Six concentration gradients were set: 0 μM, 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM, respectively. The results showed that the IC50 value of gefitinib against A549 cells was 24.42 μM.
Sotagliphology test group (FIG. 2-a-2): Cells were treated by adding Sotagliphology alone to the medium, and after incubation for 1 hour, cell viability was detected. Six concentration gradients were set: 0 μM, 10 μM, 30 μM, 40 μM, 50 μM, and 60 μM, respectively. The results showed that the IC50 value of Sotagliflodi against A549 cells was 73.04 μM.
Combined administration of gefitinib + sotagliflodi Test group 1 (Figure 2-a-3): Cells were treated by adding sotagliflodi (10 μM) and gefitinib to the culture medium, and after incubation for 1 hour, cell viability was detected. Gefitinib was treated at six different concentrations: 0 μM, 10 μM, 20 μM, 30 μM, 50 μM, and 60 μM, respectively. The results showed that the IC50 value of the test group against A549 cells was 17.03 μM.
Combined administration of gefitinib + sotagliflodi Test group 2 (Figure 2-a-4): Cells were treated by adding sotagliflodi (20 μM) and gefitinib to the culture medium, and after incubation for 2 hours, cell viability was detected. Gefitinib was treated at five different concentrations: 0 μM, 10 μM, 20 μM, 30 μM, and 40 μM, respectively. The results showed that the IC50 value of the test group against A549 cells was 12.71 μM.
Combined administration of gefitinib + sotagliflodi Test group 3 (FIG. 2-a-5): Cells were treated by adding sotagliflodi (30 μM) and gefitinib to the culture medium, and after incubation for 1 hour, cell viability was detected. Gefitinib was treated at six different concentrations: 0 μM, 10 μM, 20 μM, 30 μM, 40 μM, and 50 μM, respectively. The results showed that the IC50 value of the test group against A549 cells was 9.318 μM.
This result shows that when using the composition of sotagliflodi and gefitinib, the inhibition rate of gefitinib against A549 cells was significantly improved, and the IC50 was reduced to less than half of that of the single agent, so the combination effect of sotagliflodi within the safe concentration range It was shown that the effect of each drug was superior to that of each drug alone. For validation results of other cell lines, see Figures (2f-2j), the ability to enhance the efficacy of EGFR-TKIs targeting EGFR by co-administration with such sotagliflodi is similar to that of gefitinib as a single agent. It should be mentioned that the present invention is not limited to, and in Figure 2k, Figure 2l, the present invention further validates two other EGFR inhibitors, afatinib and erlotinib, using A549 cells as an example, and the results show that the safe and It was shown that the addition of a dose of sotagliflodi can effectively reduce the IC50 values of afatinib and erlotinib.
実施例3 ソタグリフロジとゲフィチニブの併用によるゲフィチニブに対する腫瘍細胞の薬剤耐性への逆転
1.ゲフィチニブ耐性細胞株のスクリーニング
実施例1でのゲフィチニブとソタグリフロジの併用によりゲフィチニブの有效性を顕著に増強させている知見を取得した後、本発明は、両方の併用がゲフィチニブに対する腫瘍細胞の薬剤耐性を逆転させることができるか否かを引き続き調査した。徐々に増加する濃度のゲフィチニブを含有する培地でA549細胞を長期培養すると、細胞はゲフィチニブに対する薬剤耐性を得ることができる。本発明は、5ヶ月のスクリーニングを経った後、、60μM ゲフィチニブに長期間生存できるA549ゲフィチニブ耐性細胞株を得た。
2.ソタグリフロジとゲフィチニブの併用によるゲフィチニブに対する腫瘍細胞の薬剤耐性への逆転
本発明で得られたゲフィチニブ耐性細胞株は、30μM ゲフィチニブとソタグリフロジの組成物を添加することにより該細胞株を依然として効果的に殺すことができる。これは、ソタグリフロジとゲフィチニブの併用はゲフィチニブに対する腫瘍細胞の薬剤耐性を逆転させることを示し、結果は、図3に示した。
Example 3 Reversal of drug resistance of tumor cells to gefitinib by combination of sotagliflodi and
2. Reversal of drug resistance of tumor cells to gefitinib by combination of sotagliflodi and gefitinib Gefitinib-resistant cell lines obtained in the present invention can still be effectively killed by adding a composition of 30 μM gefitinib and sotagliflodi. I can do it. This showed that the combination of sotagliflodi and gefitinib reversed the drug resistance of tumor cells to gefitinib, and the results were shown in FIG. 3.
実施例4 ソタグリフロジとアパチニブの併用
1、腫瘍細胞に対する併用投与の阻害効果
実施例1でのゲフィチニブの有效性という知見を取得した後、本発明は、他のVEGFRを標的とするVEGFR-TKI類の医薬品であるアパチニブを検証し、根据アパチニブ及びソタグリフロジの標的であるVEGFR及びSGLT1/2の組織分布特性に基づいて、本発明は、好ましくは、肝臓がん細胞株HepG2;結腸・直腸がん細胞株LoVo、HT29、SW620、SW480;子宮頸がんHeLa;卵巣がんSKOV3;胃がんHGC27;胆管がんRBE;食道がんKYSE30などを選択して実験的に検証した。その方法は、細胞が80%の密度に成長してから、トリプシン消化され、継代され、96ウェルプレートに5000cells/ウェルで塗り広げ、24時間後、対応する濃度のアパチニブ、ソタグリフロジ及びアパチニブとソタグリフロジの医薬組成物を含有する培地に交換し、48時間後、MTT法により各濃度における吸光度を検出することである。
実験は、以下の各群に分けられた。
対照群:薬物を添加せず、正常培地のみを使用して細胞を培養した。
アパチニブ被験群:培地にアパチニブのみを添加して細胞を処置し、それぞれ5μM、10μM、20μM、30μMである4つの異なる濃度を設定して処置した。
アパチニブ+ソタグリフロジの併用投与被験群:培地にソタグリフロジ(20μM)及びアパチニブを添加して細胞を処置し、アパチニブがそれぞれ5μM、10μM、20μM、30μMである4つの異なる濃度を設定して処置した。
細胞増殖阻害率は、各濃度における吸光度を対照群の吸光度で割ることにより、算出された結果を図4-a-1~図4-a-5に示した。図中では、アパチニブの濃度を横軸とし、細胞増殖阻害率を縦軸とし、結果は、腫瘍細胞に対するアパチニブ単独の阻害効果は限定的であるが、2剤併用は腫瘍に対する阻害効果を向上させるのに有利であることを示した。
Example 4 Combination of sotagliflodi and
The experiment was divided into the following groups.
Control group: Cells were cultured using only normal medium without adding drugs.
Apatinib test group: Cells were treated by adding apatinib alone to the culture medium, and were treated at four different concentrations: 5 μM, 10 μM, 20 μM, and 30 μM, respectively.
Apatinib + sotagliflodi combination test group: Cells were treated by adding sotagliflodi (20 μM) and apatinib to the culture medium, and apatinib was treated at four different concentrations: 5 μM, 10 μM, 20 μM, and 30 μM, respectively.
The cell growth inhibition rate was calculated by dividing the absorbance at each concentration by the absorbance of the control group, and the results are shown in FIGS. 4-a-1 to 4-a-5. In the figure, the horizontal axis is the concentration of apatinib, and the vertical axis is the cell growth inhibition rate. The results show that the inhibitory effect of apatinib alone on tumor cells is limited, but the combination of the two drugs improves the inhibitory effect on tumors. It was shown that it is advantageous for
2、併用投与によるIC50値の測定
2.1、肝臓がん細胞株HepG2を例として、アパチニブ+ソタグリフロジの併用投与のIC50値を検証した実験は、以下の各群に分けられた。
アパチニブ被験群(図4-b-1):培地にアパチニブのみを添加して細胞を処置し、2時間インキュベートした後、細胞生存率を検出した。それぞれ0μM、5μM、10μM、20μM、30μM、40μMである6つの濃度勾配を設定した。結果は、HepG2細胞に対するアパチニブのIC50値は46.02μMであることを示した。
ソタグリフロジ被験群(図4-b-2):培地にソタグリフロジのみを添加して細胞を処置し、2時間インキュベートした後、細胞生存率を検出した。それぞれ0μM、20μM、30μM、40μM、60μM、80μM、100μMである7つの濃度勾配を設定した。結果は、HepG2細胞に対するソタグリフロジのIC50値は115.7μMであることを示した。
アパチニブ+ソタグリフロジの併用投与被験群1(図4-b-3):培地にソタグリフロジ(10μM)及びアパチニブを添加して細胞を処置し、2時間インキュベートした後、細胞生存率を検出した。アパチニブは、それぞれ0μM、5μM、10μM、20μM、30μM、40μMである6つの異なる濃度を設定して処置した。結果は、HepG2細胞に対する該被験群のIC50値は33.3μMであることを示した。
アパチニブ+ソタグリフロジの併用投与被験群2(図4-b-4):培地にソタグリフロジ(20μM)及びアパチニブを添加して細胞を処置し、2時間インキュベートした後、細胞生存率を検出した。アパチニブは、それぞれ0μM、5μM、10μM、20μM、30μM、40μMである6つの異なる濃度を設定して処置した。結果は、HepG2細胞に対する該被験群のIC50値は29.69μMであることを示した。
アパチニブ+ソタグリフロジの併用投与被験群3(図4-b-5):培地にソタグリフロジ(30μM)及びアパチニブを添加して細胞を処置し、2時間インキュベートした後、細胞生存率を検出した。アパチニブは、それぞれ0μM、5μM、10μM、20μM、30μM、40μMである6つの異なる濃度を設定して処置した。結果は、HepG2細胞に対する該被験群のIC50値は13.13μMであることを示した。
アパチニブ+ソタグリフロジの併用投与被験群4(図4-b-6):培地にソタグリフロジ(40μM)及びアパチニブを添加して細胞を処置し、2時間インキュベートした後、細胞生存率を検出した。アパチニブは、それぞれ0μM、5μM、10μM、20μM、30μM、40μMである6つの異なる濃度を設定して処置した。結果は、HepG2細胞に対する該被験群のIC50値は10.89μMであることを示した。
この結果は、ソタグリフロジとアパチニブを併用した組成物を使用すると、HepG2細胞に対するアパチニブの阻害率が顕著に向上し、IC50が単剤の1/4以下に減少するため、ソタグリフロジの安全な濃度範囲内での併用効果が単剤のそれぞれの効果よりも優れたことを示した。他の細胞株の検証結果は、図面(4c-4g)を参照した。このようなソタグリフロジとの併用投与によるVEGFRを標的とするVEGFR-TKIの薬効への増強能力は、アパチニブの単一の薬剤に限定されないことに言及すべきであり、図5中では、本発明は、他のVEGFR阻害剤であるレンバチニブを複数種の細胞株においてさらに検証し、結果は、ソタグリフロジを安全な用量で添加することによりこれらの細胞株に対するレンバチニブの阻害効果を効果的に向上させることができることを示した。
2. Measurement of IC50 value by combined administration 2.1. Using the liver cancer cell line HepG2 as an example, an experiment to verify the IC50 value of the combined administration of apatinib + sotagliflodi was divided into the following groups.
Apatinib test group (FIG. 4-b-1): Cells were treated by adding only apatinib to the medium, and after incubation for 2 hours, cell viability was detected. Six concentration gradients were set up, each being 0 μM, 5 μM, 10 μM, 20 μM, 30 μM, and 40 μM. The results showed that the IC50 value of apatinib against HepG2 cells was 46.02 μM.
Sotagliphology test group (Figure 4-b-2): Cells were treated by adding Sotagliphology alone to the medium, and after incubation for 2 hours, cell viability was detected. Seven concentration gradients were set up: 0 μM, 20 μM, 30 μM, 40 μM, 60 μM, 80 μM, and 100 μM, respectively. The results showed that the IC50 value of Sotagliflodi against HepG2 cells was 115.7 μM.
Combined administration of apatinib + sotagliflodi Test group 1 (Figure 4-b-3): Cells were treated by adding sotagliflodi (10 μM) and apatinib to the culture medium, and after incubation for 2 hours, cell viability was detected. Apatinib was treated at six different concentrations: 0 μM, 5 μM, 10 μM, 20 μM, 30 μM, and 40 μM, respectively. The results showed that the IC50 value of the test group against HepG2 cells was 33.3 μM.
Combined administration of apatinib + sotagliflodi Test group 2 (Figure 4-b-4): Cells were treated by adding sotagliflodi (20 μM) and apatinib to the culture medium, and after incubation for 2 hours, cell viability was detected. Apatinib was treated at six different concentrations: 0 μM, 5 μM, 10 μM, 20 μM, 30 μM, and 40 μM, respectively. The results showed that the IC50 value of the test group against HepG2 cells was 29.69 μM.
Combined administration of apatinib + sotagliflodi Test group 3 (Figure 4-b-5): Cells were treated by adding sotagliflodi (30 μM) and apatinib to the culture medium, and after incubation for 2 hours, cell viability was detected. Apatinib was treated at six different concentrations: 0 μM, 5 μM, 10 μM, 20 μM, 30 μM, and 40 μM, respectively. The results showed that the IC50 value of the test group against HepG2 cells was 13.13 μM.
Combined administration of apatinib + sotagliflodi Test group 4 (Figure 4-b-6): Cells were treated by adding sotagliflodi (40 μM) and apatinib to the culture medium, and after incubation for 2 hours, cell viability was detected. Apatinib was treated at six different concentrations: 0 μM, 5 μM, 10 μM, 20 μM, 30 μM, and 40 μM, respectively. The results showed that the IC50 value of the test group against HepG2 cells was 10.89 μM.
This result shows that when a composition containing sotagliflodi and apatinib is used in combination, the inhibition rate of apatinib against HepG2 cells is significantly improved, and the IC50 is reduced to less than 1/4 of that of a single agent, which is within the safe concentration range of sotagliflodi. It was shown that the combined effect of these drugs was superior to the effects of each drug alone. For verification results of other cell lines, refer to the drawings (4c-4g). It should be mentioned that the ability to enhance the efficacy of VEGFR-TKIs targeting VEGFR by co-administration with sotagliflodi is not limited to the single agent of apatinib, and in FIG. , further validated another VEGFR inhibitor, lenvatinib, in multiple cell lines, and the results showed that the addition of sotagliflodi at a safe dose could effectively improve the inhibitory effect of lenvatinib on these cell lines. We showed what we can do.
実施例5
ソタグリフロジと併用されたTKI類医薬品が特定の1つ又は複数の医薬品に限定されないことを証明するために、他のチロシンキナーゼ阻害薬(TKI)をさらに検証した。
選ばれた医薬品は、アキシチニブ(図6-1)、ニンテダニブ(図6-2)、セジラニブ(図6-3)、パゾパニブ塩酸塩(図6-4)、スニチニブリンゴ酸塩(図6-5)、ブリバニブ(図6-6)、カボザンチニブ(図6-7)、ブリバニブアラニナート(図6-8)、レンバチニブ(図6-9)、レゴラフェニブ(図6-10)、ENMD-2076(図6-11)、チボザニブ(図6-12)、ポナチニブ(図6-13)、ENMD-2076酒石酸塩(図6-14)、テラチニブ(図6-15)、タキシフォリン(図6-16)、パゾパニブ(図6-17)、カボザンチニブリンゴ酸塩(図6-18)、ビタミンE(図6-19)、レゴラフェニブ水和物(図6-20)、ニンテダニブエタンスルホン酸塩(図6-21)、レンバチニブメシル酸塩(図6-22)、セジラニブマレイン酸塩(図6-23)、4-[(1E)-2-[5-[(1R)-1-(3,5-ジクロロ-4-ピリジル)エトキシ]-1H-インダゾール-3-イル]ビニル]-1H-ピラゾール-1-エタノール(図6-24)、スニチニブ(図6-25)、シトラバチニブ(図6-26)、アンロチニブ(図6-27)、ソラフェニブ(図6-28)、バンデタニブ(図6-29)、フルキンチニブ(図6-30)、オルムチニブ(図6-31)、オシメルチニブ(図6-32)、ゲニステイン(図6-33)、アビチニブ(図6-34)、ダコミチニブ(図6-35)、オシメルチニブメシル酸塩(図6-36)、ダフネチン(図6-37)、バルリチニブ(図6-38)、AZD3759(図6-39)、ラゼルチニブ(図6-40)、ナザルチニブ(図6-41)、リドカイン塩酸塩(図6-42)、イコチニブ(図6-43)を含んだ。
本発明は、肝臓がん細胞株HepG2を選択して実験的に検証することが好ましい。その方法は、細胞が80%の密度に成長してから、トリプシン消化され、継代され、96ウェルプレートに5000cells/ウェルで塗り広げ、24時間後、対応する濃度のアパチニブ、ソタグリフロジ及びアパチニブとソタグリフロジとの医薬組成物を含む培地に交換し、48時間後、MTT法により各濃度における吸光度を検出することである。
実験方法は、以上と同様にして、インキュベート時間が1hである。実験では、空白対照群である正常に培養されたHepG2細胞を設けられ、ここで、ソタグリフロジ又はTKI医薬品の濃度はいずれも0であり、空白対照群細胞の生存率は100%であるが、他の投与群では、使用されたソタグリフロジの濃度はいずれも30μmol/Lであり、TKI類医薬品の濃度は、表2の実験で群分けされた各群に示すようになり、結果は、図面に示した。
Example 5
Other tyrosine kinase inhibitors (TKIs) were further tested to demonstrate that the TKIs used in combination with Sotagliflodi were not limited to a specific drug or drugs.
The selected drugs are axitinib (Figure 6-1), nintedanib (Figure 6-2), cediranib (Figure 6-3), pazopanib hydrochloride (Figure 6-4), and sunitinib malate (Figure 6-5). , brivanib (Figure 6-6), cabozantinib (Figure 6-7), brivanib alaninate (Figure 6-8), lenvatinib (Figure 6-9), regorafenib (Figure 6-10), ENMD-2076 (Figure 6) -11), tivozanib (Figure 6-12), ponatinib (Figure 6-13), ENMD-2076 tartrate (Figure 6-14), teratinib (Figure 6-15), taxifolin (Figure 6-16), pazopanib ( Figure 6-17), cabozantinib malate (Figure 6-18), vitamin E (Figure 6-19), regorafenib hydrate (Figure 6-20), nintedanib ethanesulfonate (Figure 6- 21), lenvatinib mesylate (Figure 6-22), cediranib maleate (Figure 6-23), 4-[(1E)-2-[5-[(1R)-1-(3) ,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]vinyl]-1H-pyrazole-1-ethanol (Figure 6-24), sunitinib (Figure 6-25), citravatinib (Figure 6- 26), anlotinib (Figure 6-27), sorafenib (Figure 6-28), vandetanib (Figure 6-29), fruquintinib (Figure 6-30), olumtinib (Figure 6-31), osimertinib (Figure 6-32) , genistein (Figure 6-33), avitinib (Figure 6-34), dacomitinib (Figure 6-35), osimertinib mesylate (Figure 6-36), daphnetin (Figure 6-37), vallitinib (Figure 6) -38), AZD3759 (Figure 6-39), lazertinib (Figure 6-40), nazartinib (Figure 6-41), lidocaine hydrochloride (Figure 6-42), and icotinib (Figure 6-43).
It is preferable that the present invention be experimentally verified by selecting the liver cancer cell line HepG2. The method involved cells being grown to 80% confluency, then tryptic digested, passaged, and spread in 96-well plates at 5000 cells/well. After 48 hours, the absorbance at each concentration is detected by the MTT method.
The experimental method was the same as above, with an incubation time of 1 h. In the experiment, a blank control group of normally cultured HepG2 cells was provided, where the concentration of either Sotagliphology or TKI drug was 0, and the viability of blank control group cells was 100%, while other In the administration group, the concentration of Sotagliflodi used was 30 μmol/L, and the concentration of TKI drugs was as shown in each group divided in the experiment in Table 2, and the results are shown in the figure. Ta.
実施例6
実施例1~4は、いずれも細胞レベルでの試験であり、本発明で発見された糖尿病治療薬であるソタグリフロジ及びそれとTKI類医薬品によるインビボでの抗腫瘍効果をさらに検証するために、本発明は、肺がんA549細胞を選択し、その細胞について維通利華公司で生産されたBalbcヌードマウスで担がん治療試験を行った。細胞が対数増殖期まで成長すると、A549細胞を収集して無血清DMEM培地に5×107cells/mlで再懸濁し、各マウスに100μlで合計5×106個の細胞を播種し、19日間後、腫瘍サイズを計測し、サイズに基づいて群分けし、各群の腫瘍の平均サイズは同等である。群分けした後に、投与を開始し、ソタグリフロジの用量として、糖尿病患者に対する現在推奨されているソタグリフロジの1日用量は200~400mgであり、マウスへの用量に換算すると22~44mg/kgの用量で選択し、最終的に30mg/kgの用量を選択してソタグリフロジを経口投与した。ゲフィチニブは、以前の研究で報告されたA549異種移植腫瘍の治療の用量に基づいて100mg/kgの用量を特定して投与した。2つの医薬品の投与経路は、現在の臨床的な経口投与と一致してマウスに胃内投与した。投与周期は、2日1回である。腫瘍サイズは2日おきに計測された。投与40日後、試験を終了し、マウスを解剖して腫瘍を秤量した。
Example 6
Examples 1 to 4 are all tests at the cellular level, and in order to further verify the in vivo antitumor effects of Sotagliflodi, a diabetes treatment drug discovered in the present invention, and TKI drugs, the present invention was conducted. selected lung cancer A549 cells and conducted a tumor-bearing treatment test on the cells in Balbc nude mice produced by Vitong Lihua Corporation. Once the cells had grown to logarithmic phase, A549 cells were collected and resuspended in serum-free DMEM medium at 5 × 10 cells/ml, and each mouse was seeded with a total of 5 × 10 cells in 100 μl and 19 After days, tumor size is measured and divided into groups based on size, with the average size of tumors in each group being similar. After dividing into groups, administration was started, and the current recommended daily dose of Sotagliflodi for diabetic patients is 200 to 400 mg, which is equivalent to a dose of 22 to 44 mg/kg for mice. Finally, a dose of 30 mg/kg was selected and Sotagliflodi was orally administered. Gefitinib was administered at a specific dose of 100 mg/kg based on the dose reported in a previous study for the treatment of A549 xenograft tumors. The route of administration of the two drugs was intragastric administration to mice, consistent with current clinical oral administration. The administration cycle is once every two days. Tumor size was measured every 2 days. Forty days after administration, the study was terminated, the mice were dissected, and the tumors were weighed.
図7-a~図7-b~図7-cに示すように、単剤としてソタグリフロジ及びゲフィチニブはいずれも腫瘍成長を阻害することができ(図7-a~図7-b~図7-c)、ソタグリフロジとゲフィチニブの組成物は、単独で使用される2つの薬剤よりも腫瘍への阻害効果が優れたことが分かった。医薬品の有効性の評価によると、腫瘍増殖阻害率が60%を超え、且つp値が0.05未満であることを満たす必要がある。計算したところ、各群腫瘍増殖阻害率及びp値は、以上の表に示し、ソタグリフロジ及びゲフィチニブの単剤投与はいずれも無効であるが、ソタグリフロジとゲフィチニブの組成物の治療効果は有効であると最終的に判断された。
上記は、本発明の好ましい実施形態にすぎず、本発明の原理から逸脱することなく、当業者にとっては、若干の改良及び修飾を加えてもよく、これらの改良及び修飾も本発明の保護範囲に含まれることを理解すべきである。
As shown in Figures 7-a to 7-b to 7-c, both sotagliflodi and gefitinib as single agents can inhibit tumor growth (Figures 7-a to 7-b to 7-c). c) The composition of sotagliflodi and gefitinib was found to have a better inhibitory effect on tumors than the two drugs used alone. According to the evaluation of the effectiveness of a drug, it is necessary that the tumor growth inhibition rate exceeds 60% and the p value is less than 0.05. As a result of calculation, the tumor growth inhibition rate and p-value for each group are shown in the table above, and it can be concluded that the single administration of sotagliflodi and gefitinib is ineffective, but the therapeutic effect of the composition of sotagliflodi and gefitinib is effective. The final decision was made.
The above are only preferred embodiments of the present invention, and those skilled in the art may make slight improvements and modifications without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the present invention. It should be understood that this is included in
Claims (1)
前記抗腫瘍薬は、チロシンキナーゼ阻害剤であり、
前記チロシンキナーゼ阻害剤は、ENMD-2076、チボザニブ、ゲニステイン、ポナチニブ、ダフネチン、ダコミチニブ、バルリチニブ、イコチニブ、オシメルチニブメシル酸塩、オシメルチニブ、ナザルチニブ、AZD3759、アンロチニブ、アビチニブ又はラゼルチニブ、リドカイン塩酸塩、4-[(1E)-2-[5-[(1R)-1-(3,5-ジクロロ-4-ピリジル)エトキシ]-1H-インダゾール-3-イル]ビニル]-1H-ピラゾール-1-エタノール、アキシチニブ、ニンテダニブ、セジラニブ、パゾパニブ塩酸塩、スニチニブリンゴ酸塩、ブリバニブ、カボザンチニブ、ブリバニブアラニナート、レンバチニブ、レゴラフェニブ、ENMD-2076 酒石酸塩、テラチニブ、パゾパニブ、カボザンチニブリンゴ酸塩、レゴラフェニブ水和物、ニンテダニブエタンスルホン酸塩、レンバチニブメシル酸塩、セジラニブマレイン酸塩、フルキンチニブ、スニチニブ、オルムチニブ、シトラバチニブ、バンデタニブ、ゲフィチニブ、アファチニブ、アパチニブ、エルロチニブ又はソラフェニブ、タキシフォリン又はビタミンEの少なくとも1つである、
組成物。 A composition comprising sotagliflodi or a pharmaceutically acceptable salt, dimer or trimer thereof, and an anti-tumor drug for use in the treatment of cancer resistance to an anti-tumor drug, the composition comprising:
The antitumor drug is a tyrosine kinase inhibitor,
The tyrosine kinase inhibitors include ENMD-2076, tivozanib, genistein, ponatinib, daphnetin, dacomitinib, vallitinib, icotinib, osimertinib mesylate, osimertinib, nazartinib, AZD3759, anlotinib, avitinib or lazertinib, lidocaine hydrochloride, 4- [(1E)-2-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]vinyl]-1H-pyrazole-1-ethanol, axitinib, nintedanib, cediranib, pazopanib hydrochloride, sunitinib malate, brivanib, cabozantinib, brivanib alaninate, lenvatinib, regorafenib, ENMD-2076 tartrate, teratinib, pazopanib, cabozantinib malate, regorafenib hydrate, At least one of nintedanib ethanesulfonate, lenvatinib mesylate, cediranib maleate, fruquintinib, sunitinib, olmutinib, sitravatinib, vandetanib, gefitinib, afatinib, apatinib, erlotinib or sorafenib, taxifolin or vitamin E is,
composition .
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